There is a rapidly growing list of natural peptides newly isolated from human and animal tissues which are of great potency and selectivity in their biological functions. The natural peptides are generally not useful as medicinals because of rapid degradation following most delivery mechanisms. However, synthetic analogs can be designed with greater stability and with even greater potency or selectivity. The rational design of these analogs is limited by the knowledge of the active conformation for the natural peptide. These peptides are often very flexible with the number of accessible conformations increasing geometrically with the number of amino acid residues. Conformations in the receptor binding sites are virtually unknown. As a consequence, very large sets of synthetic analogs must be synthesized and tested for every newly isolated peptide before more rational refinement of the analogs can begin. This is a very laborious and expensive process. The immediate goal is to test whether one class of peptides, the enkephalins, are forced into a conformation that correlates with opiate activity when they bind to a phospholipid membrane. This is an extension of an hypothesis. There is already evidence that flexible neuropeptides are conformationally constrained when bound to model membrane systems. However, it has not yet been established that these peptide structures correlate with the biological activity. Conformations of membrane-bound enkephalins and analogs will be determined from NMR and molecular modeling studies. The analogs vary in absolute affinity for the mu- and delta-opiate receptors and in their selectivity for these receptors. The hypothesis will be supported if the results supply a quantitative correlation between conformation and these measures of activity. Given this level of success, the methods described here will be applied to a wider range of neuropeptides with conformations and analogs less well characterized than the enkephalins. Deuterium NMR of deuterated peptides bound to magnetically oriented phospholipid bilayers will remove spectral interference from the lipids and provide a simple and sensitive measure of conformation in the form of quadrupolar couplings. This approach could provide a general means for generating target structures for the rational design of new medicinal peptide mimetics.